NM_001080414.4:c.5087T>C

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_001080414.4(CCDC88C):​c.5087T>C​(p.Leu1696Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00163 in 1,485,276 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. L1696L) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0021 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0016 ( 13 hom. )

Consequence

CCDC88C
NM_001080414.4 missense

Scores

1
11
7

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:3

Conservation

PhyloP100: 8.53

Publications

6 publications found
Variant links:
Genes affected
CCDC88C (HGNC:19967): (coiled-coil domain containing 88C) This gene encodes a ubiquitously expressed coiled-coil domain-containing protein that interacts with the dishevelled protein and is a negative regulator of the Wnt signalling pathway. The protein encoded by this gene has a PDZ-domain binding motif in its C-terminus with which it interacts with the dishevelled protein. Dishevelled is a scaffold protein involved in the regulation of the Wnt signaling pathway. The Wnt signaling pathway plays an important role in embryonic development, tissue maintenance, and cancer progression. Mutations in this gene cause autosomal recessive, primary non-syndromic congenital hydrocephalus; a condition characterized by excessive accumulation of cerebrospinal fluid in the ventricles of the brain. [provided by RefSeq, Jan 2013]
CCDC88C Gene-Disease associations (from GenCC):
  • hydrocephalus, nonsyndromic, autosomal recessive 1
    Inheritance: AR Classification: STRONG, MODERATE Submitted by: Genomics England PanelApp, G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
  • spinocerebellar ataxia type 40
    Inheritance: AD Classification: MODERATE, SUPPORTIVE, LIMITED Submitted by: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.020514518).
BP6
Variant 14-91273625-A-G is Benign according to our data. Variant chr14-91273625-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 447023.We mark this variant Likely_benign, oryginal submission is: [Conflicting_classifications_of_pathogenicity].
BS2
High Homozygotes in GnomAdExome4 at 13 AR,AD gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CCDC88CNM_001080414.4 linkc.5087T>C p.Leu1696Pro missense_variant Exon 30 of 30 ENST00000389857.11 NP_001073883.2 Q9P219-1B4DZB8

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
CCDC88CENST00000389857.11 linkc.5087T>C p.Leu1696Pro missense_variant Exon 30 of 30 5 NM_001080414.4 ENSP00000374507.6 Q9P219-1
CCDC88CENST00000334448.5 linkn.899T>C non_coding_transcript_exon_variant Exon 6 of 6 1
CCDC88CENST00000556726.5 linkc.*921T>C 3_prime_UTR_variant Exon 7 of 7 5 ENSP00000452406.1 H0YJX5

Frequencies

GnomAD3 genomes
AF:
0.00207
AC:
315
AN:
152196
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000169
Gnomad AMI
AF:
0.0121
Gnomad AMR
AF:
0.00144
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00145
Gnomad FIN
AF:
0.00612
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00293
Gnomad OTH
AF:
0.00191
GnomAD2 exomes
AF:
0.00227
AC:
363
AN:
160104
AF XY:
0.00262
show subpopulations
Gnomad AFR exome
AF:
0.000149
Gnomad AMR exome
AF:
0.000611
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00505
Gnomad NFE exome
AF:
0.00284
Gnomad OTH exome
AF:
0.00436
GnomAD4 exome
AF:
0.00158
AC:
2112
AN:
1332962
Hom.:
13
Cov.:
34
AF XY:
0.00173
AC XY:
1121
AN XY:
649824
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
29046
American (AMR)
AF:
0.000614
AC:
16
AN:
26060
Ashkenazi Jewish (ASJ)
AF:
0.000259
AC:
5
AN:
19338
East Asian (EAS)
AF:
0.00
AC:
0
AN:
36608
South Asian (SAS)
AF:
0.00235
AC:
151
AN:
64128
European-Finnish (FIN)
AF:
0.00621
AC:
306
AN:
49254
Middle Eastern (MID)
AF:
0.00154
AC:
8
AN:
5208
European-Non Finnish (NFE)
AF:
0.00146
AC:
1531
AN:
1048712
Other (OTH)
AF:
0.00174
AC:
95
AN:
54608
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.487
Heterozygous variant carriers
0
110
221
331
442
552
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Exome Hom
Variant carriers
0
32
64
96
128
160
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.00207
AC:
315
AN:
152314
Hom.:
0
Cov.:
32
AF XY:
0.00213
AC XY:
159
AN XY:
74484
show subpopulations
African (AFR)
AF:
0.000168
AC:
7
AN:
41578
American (AMR)
AF:
0.00144
AC:
22
AN:
15300
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3472
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5174
South Asian (SAS)
AF:
0.00145
AC:
7
AN:
4826
European-Finnish (FIN)
AF:
0.00612
AC:
65
AN:
10624
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
294
European-Non Finnish (NFE)
AF:
0.00293
AC:
199
AN:
68022
Other (OTH)
AF:
0.00189
AC:
4
AN:
2112
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.507
Heterozygous variant carriers
0
14
28
42
56
70
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Variant carriers
0
10
20
30
40
50
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
Alfa
AF:
0.00258
Hom.:
5
Bravo
AF:
0.00132
TwinsUK
AF:
0.000270
AC:
1
ALSPAC
AF:
0.00104
AC:
4
ESP6500AA
AF:
0.000243
AC:
1
ESP6500EA
AF:
0.00119
AC:
10
ExAC
AF:
0.00216
AC:
250

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:3
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Benign:2
Jun 01, 2024
CeGaT Center for Human Genetics Tuebingen
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

CCDC88C: BS2 -

Jan 20, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

not specified Uncertain:1
Oct 31, 2016
Athena Diagnostics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

CCDC88C-related disorder Benign:1
Oct 16, 2020
PreventionGenetics, part of Exact Sciences
Significance:Likely benign
Review Status:no assertion criteria provided
Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.33
BayesDel_addAF
Benign
-0.18
T
BayesDel_noAF
Uncertain
-0.030
CADD
Pathogenic
26
DANN
Uncertain
1.0
DEOGEN2
Benign
0.20
T;T
Eigen
Uncertain
0.54
Eigen_PC
Uncertain
0.44
FATHMM_MKL
Uncertain
0.96
D
LIST_S2
Benign
0.79
T;T
M_CAP
Uncertain
0.23
D
MetaRNN
Benign
0.021
T;T
MetaSVM
Uncertain
-0.23
T
MutationAssessor
Uncertain
2.6
.;M
PhyloP100
8.5
PrimateAI
Uncertain
0.57
T
PROVEAN
Pathogenic
-6.2
D;D
REVEL
Uncertain
0.46
Sift
Uncertain
0.0010
D;D
Sift4G
Benign
0.11
T;D
Polyphen
1.0
.;D
Vest4
0.88
MVP
0.85
MPC
0.77
ClinPred
0.051
T
GERP RS
4.3
Varity_R
0.86
gMVP
0.58
Mutation Taster
=44/56
disease causing

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

Other links and lift over

dbSNP: rs77154172; hg19: chr14-91739969; COSMIC: COSV100485144; COSMIC: COSV100485144; API